With 34 million people currently living with HIV worldwide, developing a prophylactic HIV vaccine that protects against heterosexual transmission remains a top global health priority. We have recently discovered the existence of a novel class of CD8+ T cells recognizing peptide antigen presented by the non-classical molecule MHC-E. In contrast to the staggering diversity of classical HLA-A, -B, and -C alleles present in the human population, only two HLA-E alleles exist, which differ only by one amino acid and are functionally identical. Furthermore, while classical HLA-A and -B molecules are removed from the surface of HIV-infected cells by the Nef protein, HLA-E surface expression increases dramatically. These desirable traits raise the possibility that a vaccine targeting HLA-E could induce a universal T cell response, which would be unaffected by the immune evasion activities of the Nef protein, and shared by all vaccinated individuals. To investigate this intriguing idea, we will define MHC-E restricted CD8+ T cell epitopes in both humans and rhesus macaques in specific aim 1 of this proposal. In specific aim 2, we will characterize the functionality, TCR usage, and antiviral efficacy of these unusual T cells. In specific aim 3, we wil vaccinate macaques with a novel vaccine approach that delivers SIV antigens simultaneously with viral proteins identified to trigger MHC-E presentation. We will subsequently challenge these animals with low-dose SIV to determine the protective capability of MHC-E-restricted CD8+ T cells. Successful completion of these studies could define an entirely new approach to inducing universal protective immunity by mobilizing the monomorphic MHC-E molecule.